Opioid abuse remains a significant public health problem despite continued research and the availability of new drugs for treatment. In addition to the ongoing problem of heroin abuse is a growing concern about the recreational use of potent, efficacious opioid analgesics such as oxycodone. This is a competing continuation of a grant that has developed novel drug discrimination procedures for studying opioid dependence and withdrawal; those procedures have been used in concert with other measures of opioid activity to examine a range of pharmacologic and behavioral parameters that contribute to the abuse and dependence liability of morphine and related opioids. Studies proposed in this renewal exploit these discrimination procedures to focus on the neuropharmacology of opioid dependence and withdrawal as well as the role of opioid withdrawal in drug taking. AIM I characterizes the neuropharmacology of opioid withdrawal in rhesus monkeys by examining monoaminergic drugs for their ability to modulate discriminative stimulus and other effects (directly observable and HPA activation) of opioid withdrawal in monkeys. These studies build upon published data from this laboratory showing that dopamine uptake blockers attenuate discriminative stimulus and not other indices of withdrawal. AIM II combines a well-established drug discrimination procedure with i.v. self administration in monkeys to examine the effects of withdrawal on self administration of cocaine and mu agonists that vary in efficacy. AIM III provides a comprehensive set of descriptive data from rhesus monkeys on the behavioral pharmacology of several prescription opioids that are believed to be increasingly abused, including oxycodone, oxymorphone, hydrocodone and hydromorphone. While it is assumed that these opioids have exclusively morphine-like actions, there are limited data available to support that view. The four opioids will be compared to morphine using measures of drug discrimination, antinociception, and respiration. Finally, studies under AIM IV investigate the relationship between opioid tolerance and dependence, on the one hand, and constitutive activity and inverse agonism at opioid receptors, on the other hand, using drug discrimination procedures in pigeons with varying degrees of morphine tolerance and dependence. These studies should provide insight to the lasting neurobiological changes that can occur as a consequence of chronic drug treatment. Collectively these studies will apply drug discrimination and other procedures to important question regarding opioid dependence, withdrawal and abuse and will provide information that will facilitate the development of new therapeutics for opioid abuse.